Along with the progress in biotechnology in recent years, there have been a succession of discoveries of peptide roteinaceous compounds having physiological activity. Production of these compounds has become easy as well. Many of these peptide proteinaceous drugs are used only as injections due to the low level of their stability and absorbency. However, these drugs are preferably administered in multiple dosages for therapeutic reasons. Administration by injection in this case places a burden on the patient due to the pain to the patient and the need for visiting a hospital.
Therefore, other various methods of administration have been examined as non-invasive methods of administration of peptide proteinaceous drugs to take the place of injections, for example, the method of rectal administration by suppositories (J. Pharma., 33 334 (1981)), bronchial administration (Diabetes 20 552 (1971)), instillation administration (Abstracts of Diabetes Society 237 (1964)), etc. All of these methods, however, are hard to commercialize due to the difficulties that higher dosages are required than with injections and the absorption tends to fluctuate.
On the other hand, the nasal cavity has a well developed system of blood vessels in the mesothelium layer and is able to absorb a drug quickly and with little variation. Due to these advantages, the nasal administration method has come into attention. At the present time, however, sufficient absorption cannot be obtained, and therefore, various studies are under way to raise the absorbency.
For example, Nolte et al. (Hormone Metabolic Research 22, 170-174, 1990), Moses (Pharmaceutisch Week-blad-Scientific Edition 10, 45-46, 1988), Bruce et al. (Diabetic Medicine 8, 366-370,1991), etc. report on nasal administration of insulin containing sodium glycocholate or sodium taurofusidate as absorption accelerants. These preparations containing absorption accelerants, however, have problems with irritation to the nasal mucous membrane, and therefore, have not been commercialized.
As the major causes for the low absorbency of a peptide proteinaceous drug from the nasal mucous membrane, Illum (Trends Biotechnol 9, 284-289, 1991), W. A. Lee (Biopharm. Manuf. 1, 30-37, 1988), Edman (Advanced Drug Delivery Reviews 8, 165-177, 1992), etc. have mentioned the low level of drug permeability into the mucous membrane, the elimination of the drug by ciliary movement, and the degradation of the drug by the protease in the nasal cavity.
Among these, as a major discovery relating to the protease in the nasal cavity, O'Hagan et al. (Pharm. Res. 7, 772 (1990)), Hussain et al. (Pharm. Res. 6, 186 (1989)), showed by animal experiments using rats and sheep that the nasal absorption of insulin, growth hormone, enkephalin, and other peptide proteinaceous drugs is improved by administration together with amastatin, bestatin, .alpha.-aminoboronic acid, or other aminopeptidase inhibitors.
Further, Illum et al. (Japanese National Disclosure (Kohyo) No. 2-503915) mentioned that effective protease inhibitors for nasal preparations in studies of rats, rabbits, and sheep were actinonin, amastatin, bestatin, chloroacetyl-HO-Leu-Ala-Gly-NH.sub.2, diprotin A and B, evelactone A and B, E- 64, H-(tBu)-Phe-Pro-OH, kallikrein inhibitor I, chymotrypsin inhibitor I, trypsin inhibitor III- 0, leupeptin, pepstatin, phosphoramidone, aprotinin, chymostatin, and benzamidine.
Further, Morimoto et al. (111 and 112 Ann. Meetings of JPN Pharm, Soc.) showed by by animal experiments using rats that the nasal absorbency of salmon calcitonin was improved by administering it with aprotinin, TAME (tosyl arginine methyl ester), which was a synthetic substrate of trypsin, or other trypsin inhibitors.
Further, the present inventors confirmed by animal experiments using rabbits that in the nasal cavity of rabbits, salmon calcitonin, LHRH, insulin, and other peptide proteinaceous drugs were cleaved at the C terminal of the Leu in their primary structures and that the nasal absorbency of these is improved by administering them with a chymotrypsin inhibitor (for example, see Japanese Patent Application No. 5-130993 i.e., Japanese Unexamined Patent Publication No. 6-321804.
These findings, however, were all based on animal experiments using rats, sheep, and rabbits and the significance for humans is unclear. Accordingly, at the present time, it is not clear if the methods for improving the nasal absorbency of peptide proteinaceous drugs in rats, sheep, rabbits, and other animals would be effective for humans.